tbuckley/cabot-search huggingface dataset:
Allosteric Regulation of Switch-II Domain Controls KRAS Oncogenicity
Authors: Moon Hee Yang, Timothy H. Tran, Bethany Hunt, Rebecca Agnor, Christian W. Johnson, Bing Shui, Timothy J. Waybright, Jonathan A. Nowak, Andrew G. Stephen, Dhirendra K. Simanshu, Kevin M. Haigis
Journal: Cancer Research (2023)

Abstract RAS proteins are GTPases that regulate a wide range of cellular processes. RAS activity is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). KRAS can be acetylated at lysine 104 (K104), and an acetylation-mimetic mutation of K104 to glutamine (K104Q) attenuates the in vitro–transforming capacity of oncogenic KRAS by interrupting GEF-induced nucleotide exchange. To assess the effect of this mutation in vivo, we used CRISPR-Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional KrasLSL-G12D alleles. Homozygous animals for K104Q were viable, fertile, and arose at the expected Mendelian frequency, indicating that K104Q is not a complete loss-of-function mutation. Consistent with our previous findings from in vitro studies, however, the oncogenic activity of KRASG12D was significantly attenuated by mutation at K104. Biochemical and structural analysis indicated that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic KRAS. Furthermore, K104 functioned in an allosteric network with M72, R73, and G75 on the α2 helix of the switch-II region. Intriguingly, point mutation of glycine 75 to alanine (G75A) also showed a strong negative regulatory effect on KRASG12D. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant KRAS and suggest that modulating the sites in its allosteric network may provide a unique therapeutic approach in cancers expressing mutant KRAS. Significance: An allosteric network formed by interaction between lysine 104 and residues in the switch-II domain is required for KRAS oncogenicity, which could be exploited for developing inhibitors of the activated oncoprotein.
Risk Assessment of Kidney Disease Progression and Efficacy of SGLT2 Inhibition in Patients With Type 2 Diabetes
Authors: Filipe A. Moura, David D. Berg, Andrea Bellavia, Jamie P. Dwyer, Ofri Mosenzon, Benjamin M. Scirica, Stephen D. Wiviott, Deepak L. Bhatt, Itamar Raz, Mark W. Feinberg, Eugene Braunwald, David A. Morrow, Marc S. Sabatine
Journal: Diabetes Care (2023)

To develop a risk assessment tool to identify patients with type 2 diabetes (T2D) at higher risk for kidney disease progression and who might benefit more from sodium-glucose cotransporter 2 (SGLT2) inhibition.A total of 41,204 patients with T2D from four Thrombolysis In Myocardial Infarction (TIMI) clinical trials were divided into derivation (70%) and validation cohorts (30%). Candidate predictors of kidney disease progression (composite of sustained ≥40% decline in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney death) were selected with multivariable Cox regression. Efficacy of dapagliflozin was assessed by risk categories (low: <0.5%; intermediate: 0.5 to <2%; high: ≥2%) in Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58.There were 695 events over a median follow-up of 2.4 years. The final model comprised eight independent predictors of kidney disease progression: atherosclerotic cardiovascular disease, heart failure, systolic blood pressure, T2D duration, glycated hemoglobin, eGFR, urine albumin-to-creatinine ratio, and hemoglobin. The c-indices were 0.798 (95% CI, 0.774-0.821) and 0.798 (95% CI, 0.765-0.831) in the derivation and validation cohort, respectively. The calibration plot slope (deciles of predicted vs. observed risk) was 0.98 (95% CI, 0.93-1.04) in the validation cohort. Whereas relative risk reductions with dapagliflozin did not differ across risk categories, there was greater absolute risk reduction in patients with higher baseline risk, with a 3.5% absolute risk reduction in kidney disease progression at 4 years in the highest risk group (≥1%/year). Results were similar with the 2022 Chronic Kidney Disease Prognosis Consortium risk prediction model.Risk models for kidney disease progression can be applied in patients with T2D to stratify risk and identify those who experience a greater magnitude of benefit from SGLT2 inhibition.
Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib
Authors: Xiangyu Zeng, Fei Zhao, Jie Jia, Xianxiong Ma, Qi Jiang, Ruizhi Zhang, Chengguo Li, Tao Wang, Weizhen Liu, Yalan Hao, Kaixiong Tao, Zhenkun Lou, Peng Zhang
Journal: Cancer Research (2023)

Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST.BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor.
A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis
Authors: Diane E. Peters, Lauren D. Norris, Lukáš Tenora, Ivan Šnajdr, András K. Ponti, Xiaolei Zhu, Shinji Sakamoto, Vijayabhaskar Veeravalli, Manisha Pradhan, Jesse Alt, Ajit G. Thomas, Pavel Majer, Rana Rais, Christine McDonald, Barbara S. Slusher
Journal: Science Translational Medicine (2023)

There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, ( S )-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUC colon/plasma &gt; 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium–induced colitis, oral ( S )-IBD3540 inhibited &gt;75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral ( S )-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor–α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that ( S )-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule ( S )-IBD3540 is a promising approach for IBD treatment.
Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens
Authors: Jinshi Zhao, C. Skyler Cochrane, Javaria Najeeb, David Gooden, Carly Sciandra, Ping Fan, Nadine Lemaitre, Kate Newns, Robert A. Nicholas, Ziqiang Guan, Joshua T. Thaden, Vance G. Fowler, Ivan Spasojevic, Florent Sebbane, Eric J. Toone, Clayton Duncan, Richard Gammans, Pei Zhou
Journal: Science Translational Medicine (2023)

The UDP-3- O -( R -3-hydroxyacyl)- N -acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non–hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.
Perioperative Immunotherapy — A KEY toward Improved Outcomes for Early-Stage Lung Cancer?
Authors: Christine M. Lovly
Journal: New England Journal of Medicine (2023)

Lung cancer remains the leading cause of cancer-related deaths worldwide.1 However, the surge of new therapies and the use of these therapies in earlier stages of disease have generated tremendous hope for improved outcomes. In particular, immune checkpoint inhibitor therapies, with agents targeting programmed cell death protein 1 and programmed death ligand 1, administered before (neoadjuvant)2 or after (adjuvant)3,4 surgical resection, are now considered to be standard treatment options for patients with early-stage lung cancer. These treatments bring much-needed advances to an area of lung cancer medicine that has been in a drought for decades. Recently, several large clinical trials . . .
The oncomodulin receptor ArmC10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC–derived sensory neurons
Authors: Lili Xie, Yuqin Yin, Selwyn Jayakar, Riki Kawaguchi, Qing Wang, Sheri Peterson, Caleb Shi, Bruna Lenfers Turnes, Zihe Zhang, Juan Oses-Prieto, Jian Li, Al Burlingame, Clifford J. Woolf, Daniel Geschwind, Matthew Rasband, Larry I. Benowitz
Journal: Science Translational Medicine (2023)

Oncomodulin (Ocm) is a myeloid cell–derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the mechanisms underlying its activity are unknown. Using proximity biotinylation, coimmunoprecipitation, surface plasmon resonance, and ectopic expression, we have identified armadillo-repeat protein C10 (ArmC10) as a high-affinity receptor for Ocm. ArmC10 deletion suppressed inflammation-induced axon regeneration in the injured optic nerves of mice. ArmC10 deletion also suppressed the ability of lesioned sensory neurons to regenerate peripheral axons rapidly after a second injury and to regenerate their central axons after spinal cord injury in mice (the conditioning lesion effect). Conversely, Ocm acted through ArmC10 to accelerate optic nerve and peripheral nerve regeneration and to enable spinal cord axon regeneration in these mouse nerve injury models. We showed that ArmC10 is highly expressed in human-induced pluripotent stem cell–derived sensory neurons and that exposure to Ocm altered gene expression and enhanced neurite outgrowth. ArmC10 was also expressed in human monocytes, and Ocm increased the expression of immune modulatory genes in these cells. These findings suggest that Ocm acting through its receptor ArmC10 may be a useful therapeutic target for nerve repair and immune modulation.
The Social Determinants of Health — Moving Beyond Screen-and-Refer to Intervention
Authors: Rahul Vanjani, Neha Reddy, Nicole Giron, Eric Bai, Sarah Martino, Megan Smith, Suzanne Harrington-Steppen, M. Catherine Trimbur
Journal: New England Journal of Medicine (2023)

As we increasingly recognize the profound effects of social determinants of health, clinicians and health systems should understand the unique power they hold with regard to social care.
Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome
Authors: Wen Y. Ding, Valeryia Kuzmuk, Sarah Hunter, Abigail Lay, Bryony Hayes, Matthew Beesley, Ruth Rollason, Jennifer A. Hurcombe, Fern Barrington, Catrin Masson, William Cathery, Carl May, Jack Tuffin, Timothy Roberts, Geraldine Mollet, Colin J. Chu, Jenny McIntosh, Richard J. Coward, Corinne Antignac, Amit Nathwani, Gavin I. Welsh, Moin A. Saleem
Journal: Science Translational Medicine (2023)

Gene therapy for kidney diseases has proven challenging. Adeno-associated virus (AAV) is used as a vector for gene therapy targeting other organs, with particular success demonstrated in monogenic diseases. We aimed to establish gene therapy for the kidney by targeting a monogenic disease of the kidney podocyte. The most common cause of childhood genetic nephrotic syndrome is mutations in the podocyte gene NPHS2 , encoding podocin. We used AAV-based gene therapy to rescue this genetic defect in human and mouse models of disease. In vitro transduction studies identified the AAV-LK03 serotype as a highly efficient transducer of human podocytes. AAV-LK03–mediated transduction of podocin in mutant human podocytes resulted in functional rescue in vitro, and AAV 2/9–mediated gene transfer in both the inducible podocin knockout and knock-in mouse models resulted in successful amelioration of kidney disease. A prophylactic approach of AAV 2/9 gene transfer before induction of disease in conditional knockout mice demonstrated improvements in albuminuria, plasma creatinine, plasma urea, plasma cholesterol, histological changes, and long-term survival. A therapeutic approach of AAV 2/9 gene transfer 2 weeks after disease induction in proteinuric conditional knock-in mice demonstrated improvement in urinary albuminuria at days 42 and 56 after disease induction, with corresponding improvements in plasma albumin. Therefore, we have demonstrated successful AAV-mediated gene rescue in a monogenic renal disease and established the podocyte as a tractable target for gene therapy approaches.
Case 24-2023: A 43-Year-Old Man with a Pulmonary Nodule
Authors: Angela J. Frank, Jo-Anne O. Shepard, Inga T. Lennes, Lana Y. Schumacher, Angela R. Shih
Journal: New England Journal of Medicine (2023)

A 43-year-old man was evaluated because of a lung nodule. A PET scan showed FDG uptake in the nodule and adjacent lymph nodes. A diagnostic test was performed.
Age, Sex, and Outcomes in Heart Failure With Reduced EF
Authors: Carolyn S.P. Lam, Ileana L. Piña, Yinggan Zheng, Diana Bonderman, Anne-Catherine Pouleur, Clara Saldarriaga, Burkert Pieske, Robert O. Blaustein, Richard Nkulikiyinka, Cynthia M. Westerhout, Paul W. Armstrong
Journal: JACC Heart Failure (2023)
Frailty Status Modifies the Efficacy of ICD Therapy for Primary Prevention Among Patients With HF
Authors: Matthew W. Segar, Neil Keshvani, Sumitabh Singh, Lajjaben Patel, Shyon Parsa, Traci Betts, Gordon R. Reeves, Robert J. Mentz, Daniel E. Forman, Mehdi Razavi, Mohammad Saeed, Dalane W. Kitzman, Ambarish Pandey
Journal: JACC Heart Failure (2023)
Covalent Organic Framework‐Based Nanomotor for Multimodal Cancer Photo‐Theranostics
Authors: Jie Feng, Shi‐Peng Yang, Yu‐Qing Shao, Yun‐Yu Sun, Zi‐Liang He, Ying Wang, Ya‐Nan Zhai, Yu‐Bin Dong
Journal: Advanced Healthcare Materials (2023)

Developing efficient integrated diagnosis and treatment agents based on fuel-free self-movement nanomotors remains challenging in antitumor therapy. In this study, a covalent organic framework (COF)-based biomimetic nanomotor composed of polypyrrole (PPy) core, porphyrin-COF shell, and HCT116 cancer cell membrane coating is reported. Under near-infrared (NIR) light irradiation, the obtained mPPy@COF-Por can overcome Brownian motion and achieves directional motion through self-thermophoretic force generated from the PPy core. The HCT116 cancer cell membrane coating enables the nanomotor to selectively recognize the source cell lines and reduces the bio-adhesion of mPPy@COF-Por in a biological medium, endowing with this NIR light-powered nanomotor good mobility. More importantly, such multifunctional integration allows the COF-based nanomotor to be a powerful nanoagent for cancer treatment, and the high infrared thermal imaging/photoacoustic imaging/fluorescence trimodal imaging-guided combined photothermal/photodynamic therapeutic effect on HCT116 tumor cell is successfully achieved. The results offer considerable promise for the development of COF nanomotors with integrated imaging/therapy modalities in biomedical applications.
Validation of the Proposed International Association for the Study of Lung Cancer Residual Tumor Classification to Upgrade Extracapsular Extension of Tumor in Nodes From R0 to Incomplete Resection
Authors: Huikang Xie, Chenyang Dai, Chang Gu, Shengnan Zhao, Long Xu, Fang Wang, Jiani Gao, Hang Su, Junqi Wu, Yunlang She, Yijiu Ren, Chunyan Wu, Chang Chen
Journal: Journal of Thoracic Oncology (2023)
Telomere length and chronological age across the human lifespan: A systematic review and meta-analysis of 414 study samples including 743,019 individuals
Authors: Qiaofeng Ye, Abner T. Apsley, Laura Etzel, Waylon J. Hastings, John T. Kozlosky, Cade Walker, Sarah E. Wolf, Idan Shalev
Journal: Ageing Research Reviews (2023)
P845: DECIPHERING PLASMA CELL HETEROGENEITY AND TRANSCRIPTOME FEATURES IN POEMS SYNDROME USING SINGLE CELL RNA-SEQUENCING
Authors: Haiyan He, XI Chen, Nan Hou, Jin Liu, Wanting Qiang, Jing Lu, Lina Jin, Xiaoqiang Fan, Juan Du
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. Little is known about its pathogenesis and transcriptome features, and information distinguishing PCs from POEMS syndrome and multiple myeloma (MM) patients is sparse by far. Aims: The main objective of this study was to decipher the underlying disease mechanisms of the POEMS syndrome at cellular and molecular level by analyzing bone marrow (BM) samples from POEMS syndrome patients using single cell RNA sequencing (scRNAseq). To achieve this, we aimed to compare heterogeneity within POEMS vs MM plasma cells at the cellular and gene expression level. Methods: Bone marrow samples from 4 POEMS syndrome patients and 4 MM patients were analyzed. The BM-Mononuclear cells (MNCs) were sorted based on their CD138 expression. The Chromium Single Cell 5’RNAseq run and library preparation were done using Chromium™ Single Cell 5’ Reagent version 3 chemistry. 10x Genomics CellRanger v3.0.1 pipeline was used for the raw data processing. Further, the quality control and cell type clustering was finished with a R package Seurat 4.1.0. Cell type annotation was identified by specific cell type markers which was obtained from sctype database, MSigDB and manual curation. Results: From the integrated analysis of all 8 scRNAseq data, we identified a total of 6 functional clusters of BMPCs (PC1-PC6), among which PC1 and PC5 were enriched by cells from POEMS syndrome samples (Fig.1). The top-ranked expressed genes were immunoglobulin heavy chain and light chain V segments (IGHV and IGLV/IGKV) for the six clusters. For PC1 the most frequent usage of λ variable (V) domains were IGLV1-47, IGLV1-40 and IGLV3-1. When filtering out IGHV and IGLV/IGKV, we found the clusters enriched by plasma cells from POEMS syndrome showed up-regulated genes such as HBB, TMEM238, and HBA2 for PC1, and RPS10, CD27 and TMEM156 for PC5. Moreover, we analyzed the plasma cell clonotypes through single-cell V(D)J sequencing data, and we found samples from POEMS syndrome patients contained a large number of polyclonal plasma cells as well as monoclonal plasma cells, while almost all the plasma cells from MM patients were monoclonal plasma cells. Summary/Conclusion: This is the first study to reveal functional clusters of BMPCs which provide mechanistic insights into POEMS syndrome pathogenesis, and may find some potential biomarkers for targeted therapy. Figure 1Keywords: Plasma cells, RNA-seq
PB2669: PCR‐RFLP ASSAY FOR THE DETECTION OF THROMBOPHILIC GENE POLYMORPHISMS
Authors: Nouha Bouayed Abdelmoula
Journal: HemaSphere (2023)

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Thrombophilia is defined by clinical situations characterized by the occurrence of recurrent venous thrombosis or biological hypercoagulability. It may be associated at the genetic level with recurrent mutations and polymorphisms in certain coagulation factor genes, including the G20210A mutation, also known as the Leiden mutation. Aims: In this study, we aimed to explore a panel of PCR‐RFLP methods for identifying thrombophilic genes polymorphisms. Methods: Mutations in factor V 1691G<A and prothrombin (coagulation factor II) gene 20210 G>A as well as MTHFR polymorphisms 677 C>T and 1298 A>C were targeted. Primer pairs were selected for touch down PCR amplification of exon 10 of the F5 gene, the 3’UTR region of the factor II gene and exons 4 and 7 of the MTHFR gene, respectively. Enzymatic digestions were performed using two restriction enzymes MnlI for F5 and F2 amplification products, and HinfI and MboII for MTHFR amplicons. Results: The PCR-RFLP reactions of the four fragments containing the polymorphisms of interest in our study revealed several types of profiles according to the presence or absence of the polymorphism and according to its homozygous or heterozygous status. Summary/Conclusion: The technical assay developed for the identification of RFLP markers of thromboembolic disease are reproducible, simple and inexpensive. Their use in both biological practice and basic research remains relevant. Keywords: Thrombophilia, Polymorphism, Polymerase chain reaction